Autism is a neurodevelopmental disorder characterized by severe ritualistic-repetitive behaviors, impaired social interaction, and impaired communication/language. Autism generally manifests in infancy, with most affected children experiencing nearly complete social detachment, persistent impairment, and therefore requiring life-long supervision. Family studies have demonstrated that autism is highly heritable, and linkage studies from our group and others have identified a number of putative genetic susceptibility loci. Language impairment interacts prominently with these findings, as evidenced by linkage studies, from our sample and others, of subgroups of autistic families with severe language impairment, and by overlapping linkage findings from families segregating various speech and language disorders. Based on this, members of our research group recently reported evidence suggesting that WNT2, a developmentally expressed brain patterning gene, is an autism susceptibility gene. We propose in this application to build on our existing body of work, further pursuing our primary goal of identifying autism disease genes. This will be accomplished by: 1) examining candidate disease genes from three chromosomal regions of interest (ROI), 2) performing sophisticated cytogenetic analyses on a cohort of 500 autistic individuals, and 3) further examination of WNT2 as an autism susceptibility gene. The gene screening will be performed using multiple patient samples with complementary phenotypes showing overlapping linkages to each ROI, and each gene will be comprehensively examined using a variety of approaches. This molecular work will be supported by our high-throughput sequencing and screening capabilities, state-of-the-art bioinformatics laboratory, and our recently formed Center for Statistical Genetics Research. The cytogenetic examination will also be comprehensive, incorporating the latest methods for detecting previously undetectable chromosomal abnormalities, and supported by an extensive clinical network and a well-established regional cytogenetics laboratory. The WNT2 findings will be further examined in two-independent patient samples.